The role of hypothalamic peptide hormone with special emphasis on the melanotropin release inhibiting factor (MIF) and thyrotropin releasing hormone (TRH) in the regulation of acute (analygesia, hypothermia, catalepsy, locomotor activity, etc.) and chronic effects (tolerance and physical dependence) of opiates will be investigated. In addition to the naturally occurring hormones, which have short biological half life, studies will be carried out with their synthetic analogs. The opiates will include endogenous (endorphins) and exogenous [morphine type (agonists) and buprenorphine (agonist-antagonist type)] opiates. Tolerance to and physical dependence on morphine type analgesics will be induced by the pellet implantation procedure, whereas, the endorphins will be injected chronically via indwelling cannulae in the brain. Tolerance will be assessed by measuring the analgesic, hypothermia, cataleptic and locomotor effects to a challenge dose of an opiate in tolerant and nontolerant rats. The degree of physical dependence will be measured by determining the intensity of hypothermia, body weight loss observed during abrupt and antagonist-induced withdrawal and also the intensity of stereotyped jumping syndrome seen after precipitated withdrawal. Our studies indicate that it is possible to block the development of tolerance to narcotic drugs with some peptides. The mechanism by which this effect is produced will be investigated by examining the activity of brain enkephalinases, and various receptor systems including those for MIF and TRH. These studies may provide drugs related to the naturally occurring peptides, which when used concomitantly with opiates to relive pain may no longer produce tolerance and physical dependence.